Current WHO recommendation to reduce free sugar intake from all sources to below 10% of daily energy intake for supporting overall health is not well supported by available evidence

ABSTRACT Sugar is widely consumed over the world. Although the mainstream view is that high added or free sugar consumption leads to obesity and related metabolic diseases, controversies exist. This narrative review aims to highlight important findings and identify major limitations and gaps in the current body of evidence in relation to the effect of high sugar intakes on health. Previous animal studies have shown that high sucrose or fructose consumption causes insulin resistance in the liver and skeletal muscle and consequent hyperglycemia, mainly because of fructose-induced de novo hepatic lipogenesis. However, evidence from human observational studies and clinical trials has been inconsistent, where most if not all studies linking high sugar intake to obesity focused on sugar-sweetened beverages (SSBs), and studies focusing on sugars from solid foods yielded null findings. In our opinion, the substantial limitations in the current body of evidence, such as short study durations, use of supraphysiological doses of sugar or fructose alone in animal studies, and a lack of direct comparisons of the effects of solid compared with liquid sugars on health outcomes, as well as the lack of appropriate controls, seriously curtail the translatability of the findings to real-world situations. It is quite possible that “high” sugar consumption at normal dietary doses (e.g., 25% daily energy intake) per se—that is, the unique effect of sugar, especially in the solid form—may indeed not pose a health risk for individuals apart from the potential to reduce the overall dietary nutrient density, although newer evidence suggests “low” sugar intake (<5% daily energy intake) is just as likely to be associated with nutrient dilution. We argue the current public health recommendations to encourage the reduction of both solid and liquid forms of free sugar intake (e.g., sugar reformulation programs) should be revised due to the overextrapolation of results from SSBs studies.


Introduction
Obesity, defined as having a BMI greater than or equal to 30 kg/m 2 , is a risk factor for various metabolic and endocrine abnormalities, such as hyperglycemia, hypertension, and dyslipidemia (1). The prevalence of obesity has increased dramatically in the past decades and is now considered an epidemic (1). High sugar consumption has been suggested to be obesogenic by inducing overeating and weight gain (2), and is considered a risk factor for chronic diseases, such as type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) (3)(4)(5). In 2015, the WHO released a new recommendation of reducing the intake of free sugars, defined as sugar added to foods during production or cooking plus sugars found in honey, syrups, and fruit juices, to <10% of the daily energy intake, with a stricter target of <5% of daily energy intake for additional health benefits. The aim of this new recommendation on sugar was to reduce risks of all chronic diseases, especially for the prevention and control of obesity and dental caries (6).
The prevailing consensus among academics and public health practitioners is that high free sugar consumption is associated with ill health, as well as overweight and obesity, based on the concordance of available evidence from several sources (2,3), as well as conclusions from systematic reviews and metaanalyses of available studies (7,8). Nonetheless, it is a widely acknowledged fact that the publication of positive findings faces less resistance from journal reviewers and editors than that for null findings (9)(10)(11), and hence conclusions related to the free sugar-health relationship drawn from the literature may be somewhat affected by publication bias on an adverse association between the 2.
When examined carefully, it appears that most studies linking high free sugar intake to ill health focused on sugars from sugarsweetened beverages (SSBs) (12)(13)(14), while studies examining free sugars from solid sources mostly reported null findings (15,16). This has led to controversies regarding whether high free sugar consumption is detrimental to health, with some researchers suggesting that sugars are merely a source of calories, similar to proteins and fats (17). It also begs the question of whether the current public health recommendation to reduce free sugar intake from all sources (i.e., both solids and liquids) is well supported by the available evidence.
Therefore, in this review, we will highlight the limitations and problems in the current body of evidence, which may undermine the strength of study conclusions. We also propose that a rethink of whether all forms of free sugars are uniquely associated with ill health is warranted.

Criteria of human study selection
For human studies (observational studies and clinical trials) to be considered eligible for inclusion, they had to meet the following criteria: 1) involved adult or children participants, who were either normal weight or overweight or obese at baseline; 2) examined high-sugar diets in the form of solids, liquids, or both; and 3) measured outcomes indicative of metabolic and endocrine health, such as body weight, fasting blood glucose and insulin levels, blood lipid levels, fat mass, and blood pressure. We imposed no restriction on the year of publication and included only articles in the English language. Reports such as unpublished manuscripts and conference abstracts were not included.

Different metabolic consequences of intakes of glucose and fructose
Free sugars in the diet mostly come in the form of sucrose, which is digested into glucose and fructose in the gastrointestinal tract for absorption, as well as high-fructose corn syrup (HFCS), which contains a ∼1:1 ratio of glucose and fructose as monosaccharides (18). The metabolic fates of the 2 absorbed monosaccharides are different. The glucose metabolism is tightly regulated by insulin and hepatic energy statuses (19), where most postprandial glucose from the normal dietary intake will be metabolized in peripheral tissues, leaving little for storage as fat in the liver, thereby comprising a lower risk of developing chronic diseases, such as insulin resistance and T2DM, compared to fructose. Unlike glucose, the fructose metabolism is not regulated by insulin and hepatic energy needs, as the conversion to fructose 1-phosphate bypasses the key regulatory enzyme phosphofructose kinase-1 (20). Also, fructose does not stimulate insulin secretion (21), probably because of the absence of glucose transporter (GLUT) 5 in pancreatic β-cells (22). Thus, most fructose will be metabolized and stored by the liver, with little metabolism in peripheral tissues. It will also induce de novo lipogenesis (DNL) (23), resulting in hepatic fat accumulation (24), as well as insulin resistance and increased gluconeogenesis (19). Insulin resistance will further promote hepatic DNL, resulting in a vicious cycle that elevates VLDL production and secretion. Consequently, the plasma triglyceride (TG) concentration is even higher, leading to lipid accumulation in skeletal muscle, impaired insulin action, and whole-body insulin resistance (19). Additionally, the lack of insulin secretion after fructose ingestion also reduces leptin secretion by adipocytes (19), which may increase food intake, leading to weight gain and obesity (19,22). It has also been proposed that high sugar consumption is detrimental for health due to its glycemic effects (25). However, only the glucose component of sugars has a high glycemic index (GI), while fructose has a low GI and sucrose has a moderate GI (26). Moreover, it has been suggested that the GIs of most highsugar foods are low to moderate (27). Therefore, the glycemic effects of sugars per se should not have a major influence on cardiometabolic health. Overall, theoretically, excessive added or free sugar consumption could increase the risks of metabolic diseases through the direct actions of its constituent sugars and induction of weight gain indirectly (19), although whether this will happen at typical dietary doses remains controversial.
Free sugars from solid compared with liquid foods: differential effects on health?
As mentioned earlier, much of the available evidence supporting weight gain in humans after high sugar consumption comes from studies focusing on SSBs (12)(13)(14), and few studies have directly compared the obesogenic effects of sugar in a solid compared with liquid form (19). This is important because studies have suggested that liquid sugar could elicit overeating, followed by incomplete compensation at subsequent meals, whereas solid sugar may not promote a positive energy balance (15,16), despite most solid foods high in sugar also being high in energy density (28). Besides the difference in state (liquid vs. solid), there are also other differences which could contribute to the discrepancies in effects on metabolic health of solid compared with liquid sugars, such as the presence of caffeine (29), carbonation (30), and caramel colorings in some SSBs and in cola beverages (31). There have also been some observational studies conducted in children showing that SSB consumption leads to a higher risk of metabolic syndrome (MetSyn) than eating sugars in solid foods (32)(33)(34)(35)(36)(37). For example, in a prospective cohort study conducted in African American and White children from the National Heart, Lung, and Blood Institute Growth and Health Study (n = 2021 at baseline; n = 5156 paired observations), after controlling for total energy intake, increased intake of liquid sugars was associated with an increase in waist circumference in all children over the 1-year follow-up period, whereas increased consumption of solid sugars was associated with an increased waist circumference in obese children only (32). In a prospective cohort study in Danish children from the European Youth Heart Study (n = 359), over the 6-year follow-up period, increased intake of liquid sugars predicted an increase in waist circumference and BMI, independent of energy intake, whereas intake of solid sugars did not (33). Intake of liquid but not solid sugars was associated with higher fasting glucose and insulin levels in Canadian Caucasian children in a prospective cohort study, as well as insulin resistance over the 2-year follow-up period after controlling for energy intake and physical activity (n = 630) (34). Higher intake of liquid but not solid sugars was linked with higher BMIs in girls (n = 1172) but not boys (n = 967) in Finnish children in a prospective cohort study, over the 21-year follow-up period (36).
In Australian children, intake of liquid sugars was associated with a greater BMI over the 3.5-year follow-up period in a prospective cohort study (n = 158), compared with null findings in solid sugar (37).
A recent review of 7 epidemiological studies and 1 crossover clinical trial (38) concluded that SSBs may be more likely to induce MetSyn than sugars in solid foods. The faster gastric emptying time for liquid sugars, and consequently the higher absorption of the fructose moiety, may lead to fat accumulation in the liver. Consumption of SSBs induces satiety less than solid sugar sources and is more likely to cause overeating or incomplete energy compensation at subsequent meals (39). This is important because the intestine may convert fructose to glucose when low concentrations are consumed, but fructose is transported to the liver more easily when consumed in high concentrations, such as from SSBs (40).

Adverse health effects and proposed mechanisms of action: evidence from animal studies
Our concerns regarding the adverse health effects of high sugar consumption likely originated from animal studies. Mice or rats have been used to identify the culprits of potential detrimental health effects associated with high sugar intake (41,42), as their genomes and organ systems are similar to those of humans, and they develop diseases in a comparable way to humans (43). However, mice and rats do differ from humans in the intermediary metabolism (44), which may undermine the translatability of rodent findings to advance human health (45). Therefore, conclusions from animal studies should be interpreted with caution.
Sucrose or fructose feeding of supraphysiological doses in both solid and liquid forms has been shown to induce insulin resistance, glucose intolerance, hyperglycemia, and hypertriglyceridemia in animals, mostly over the short term ( Table 1) (46)(47)(48)(49)(50)(51). For example, feeding rats with a high-sucrose diet (69% daily energy intake of a 74-kcal diet) for 4 weeks led to insulin resistance in the liver, compared to an isocaloric high-starch diet (n = 55) (51). Administration of a high-sucrose diet [68% weight by weight (w/w)] in rats for 1, 2, 5, or 8 weeks significantly impaired insulin action in the liver and muscle, and increased serum TG concentrations, compared with the starch control diet, which may be associated with insulin resistance (n = 8-10 per group per time point) (49). In another study, rats fed a 60% w/w fructose diet developed hyperglycemia and hyperinsulinemia when compared with the control group in 8 weeks (n = 24) (52).
Results from longer-term studies on sugar in solid foods are similar. For example, rats that consumed a 63% w/w high-sucrose diet for 30 weeks developed hyperglycemia, hypertriglyceridemia, and insulin resistance, compared to the control group fed on an isocaloric high-starch diet (n = 16) (48). Interestingly, insulin secretion was not increased in the presence of pancreatic hypertrophy and hyperplasia, and there was also some β-cell derangement (48). Ruff et al. (50) showed that in wild-type mice, high sugar consumption (at 25% daily energy intake) for 26 weeks resulted in increased mortality in females (n = 98) and decreased controlled territories and reproductive success in males (n = 58), in addition to reducing glucose tolerance and increasing fasting cholesterol level in both sexes.
The effects of high sugar consumption in the liquid form on top of the standard lab chow diet were examined in 2 studies (46,47). In 1 study, feeding 32% w/w fructose or sucrose solutions in addition to the standard lab chow to rats for 50 days led to reduced glucose tolerance, and significantly a higher TG concentration was also observed in those given a 32% w/w fructose solution, compared to rats given a 32% w/w glucose solution (46). Similarly, Lee et al. (47) also showed that supplementation of the standard lab chow diet with SSBs resulted in significantly higher fasting glucose levels, as well as accumulation of lipids in the liver. Expression of inflammatory genes in the liver and adipose tissues also increased (n = 40).
Overall, feeding excessive sugar (fructose or sucrose) to mice or rats, whether in solid or liquid form, could cause reduced competitive ability and metabolic abnormalities, including insulin resistance, hyperglycemia, and hypertriglyceridemia. These health effects are likely associated with the development of obesity.

Limitations of previous animal studies.
While conclusions from animal studies generally support the adverse health effects of high sugar consumption, caution should be exercised in interpreting and translating the results, as several major limitations exist, which might explain why all studies, regardless of whether solid or liquid sugars were examined, found negative health effects of high sucrose or fructose consumption.
First, some studies used fructose alone as the treatment. However, fructose is rarely consumed alone in the human diet. Instead, it almost always coexists together with glucose in the form of sucrose or HFCS. Since the metabolism of pure fructose and its associated health consequences is different from when fructose is consumed as part of sucrose or consumed with glucose (as in HFCS) (41), it is a far reach to translate the conclusions related to excessive pure fructose consumption in rodents into the human situation. Also, most animal studies failed to include a control group where only glucose was consumed; therefore, it is unknown whether the adverse health effects observed are due to the high monosaccharide (fructose) consumption per se or to the energy supplied by fructose specifically (41,42,53).
Second, the majority of studies examined the health impacts of supraphysiological doses of sugars (typically >50% of the daily energy intake). These studies were designed to induce pronounced metabolic impairments in a short period, to investigate the mechanisms of action in laboratory animals. However, results obtained from such studies bear little resemblance to actual human consumption levels (54). Third, in designing the control diet, most studies opted to replace all sugars with starch, which is unrealistic and irrelevant to humans, as we rarely consume a diet devoid of sugars. On average, adults consume between 7% and 12% of their daily energy intake from added sugars (55). Fourth, no studies so far have directly compared the effects of solid compared with liquid sugars on metabolic and endocrine health in rodents, which makes it difficult to draw firm conclusions regarding the potential differences in their effects on metabolic and endocrine health. Last, while some rodent studies lasted more than 20 weeks, which covers a substantial period of a rodent's life span, most studies were conducted over a short period and rarely 55 male Wistar rats 4 wk Starch diet (0% daily energy intake from sugar) vs. SRD (69% daily energy intake), at 74 kcal/d The SRD resulted in impairment in whole-body glucose disposal, due mainly to impairment in hepatic insulin action. However, it did not affect body fat accumulation 1 HFD, high-fat diet; HFrD, high-fructose diet; SSB, sugar-sweetened beverage; SRD, sucrose-rich diet; TG, triglyceride; w/w, weight/weight. lasted longer than 6 to 8 weeks, thus impairing translatability into humans.

Studies on high sugar consumption and metabolic or endocrinic disturbances in humans
Evidence from observational studies.
Unlike in animal studies, there is great heterogeneity in the conclusions from observational studies in humans, with some supporting an association between high SSBs or sugar consumption and the development of metabolic diseases, while others report null findings (Tables 2 and 3). This might be due to differences in study designs, populations of interest, and the forms of sugar examined (e.g., SSBs vs. solid sugar). Also, many observational studies collect data via self-reporting of the participants: for example, from FFQs, dietary record, and dietary recalls (56,57). Self-reported dietary data are often regarded as being unreliable, as they may be affected by selective recall and reverse causation. Differences in confounding factors across observational studies are also a concern, and they affect the abiltabity to synthesize evidence from various studies. Nonetheless, based on the Bradford Hill criteria, causality can be assumed only between SSB intakes and cardiometabolic disease risks, as most if not all studies showed consistent results; however, no causality can be assumed between total, added, and free sugar intakes and health outcomes, as results are largely inconsistent. Furthermore, it has been proposed that the Bradford Hill criteria should be adapted to the evolving nature of research to promote multidisciplinary research and data integration frameworks (58). Caution should therefore be exercised in interpreting findings from observational studies.
Several prospective cohort studies have shown that high sucrose or fructose consumption was not associated with the T2DM incidence or risks (86,(91)(92)(93)(94)(95)(96), nor was it even associated with a reduced risk of T2DM (78,91,97,98) (Table 3). In contrast, Warfa et al. (80) showed in a prospective cohort study that high sucrose consumption was associated with an increased risk of T2DM, and the study by Montonen et al. (77) showed high fructose intake, but not sucrose intake, was associated with an increased T2DM incidence. For cardiometabolic health, studies (77,78,86,91,93,94,96,(99)(100)(101) have shown that high intakes of both sucrose or fructose and total sugars were not associated with increased risks of total CVD, total CHD, or total stroke. Results were inconsistent for CVD or all-cause mortality, with some studies suggesting an adverse association between added sugar and mortality (79,102), while Tasevska et al. (103) reported null findings in women or even a protective effect in men.
These observed associations could be due to both direct (unique metabolic changes induced by fructose, such as increased hepatic DNL without inducing weight gain) and indirect (promotion of weight gain and obesity, leading to adverse metabolic effects) effects of fructose (22). In a prospective cohort study conducted in an Asian population (n = 43,580) (72), high soft drink consumption was associated with increased risk of T2DM, independently of changes in BMI, and weight gain in addition to high soft drink consumption exerted an additive effect on increasing risk of T2DM. Similarly, regular SSB consumption was associated with higher C-reactive protein (CRP) levels (104), and this association was strengthened by obesity (89), whereas sugars from solid foods were not associated with increased CRP levels (104). In another prospective cohort study conducted by Tasevska et al. (103) (n = 353,751), high total fructose but not added sugar consumption in both males and females was found to be related to a modest increase in the all-cause mortality risk. This was only restricted to fructose in SSBs, not fructose present in solid foods, which is in line with the conclusions by Togo et al. (16) and DiMeglio and Mattes (15). However, high intake of free or added sugars was found to be positively associated with all-cause mortality in the prospective cohort study conducted by Ramne et al. (79). Moreover, high consumption of solid sugar sources was inversely associated with all-cause mortality, and high intake of SSBs was positively associated with all-cause mortality (79). Similarly, in the prospective cohort study (n = 25,877) by Janzi et al. (71), while high added sugar intake was associated with increased risks of coronary events and stroke and high SSB consumption was associated with an increased risk of stroke, low added sugar intake was found to increase the risks of aortic stenosis and atrial fibrillation and low consumption of sugar-sweetened solid foods increased the risks of stroke, coronary events, and atrial fibrillation. All these studies support the differential effects of liquid compared with solid forms of carbohydrates in inducing overeating and obesity (liquid > solid). High SSB consumption may also be implicated in the pathogenesis of NAFLD, as shown in a crosssectional study (n = 73) (105), in addition to being implicated in hypertriglyceridemia (prospective cohort study; n = 2774) (70).
Overall, the findings from observational studies remain inconclusive. Our views agree with a previous systematic review of prospective cohort studies (106), which concluded that high SSB consumption increases the risk of cardiovascular diseases both directly and indirectly through weight gain. Additionally, in a recent meta-analysis of 11 prospective cohort studies that assessed the associations between SSB intake and risks of CVD and mortality (102), long-term consumption of SSBs was dose-dependently associated with increased risks of CVD morbidity and mortality. Similarly, in another meta-analysis of 24 observational studies (12 longitudinal studies, 11 cross-sectional studies, and 1 case-control study) (107), high SSB intake was associated with an increased risk of MetSyn compared to low          SSB consumption. The meta-analysis of 11 prospective cohort studies also showed that participants in the highest quantile of SSB consumption (most often 1-2 servings/day) had greater risks of developing T2DM and MetSyn compared to those in the lowest quantile of SSB consumption (0 or <1 serving/month) (108). However, high SSB consumption was only associated with the development of MetSyn in a pooled analysis of cross-sectional studies, not in prospective cohort studies, in the systematic review and meta-analysis of 8 cross-sectional and 4 prospective cohort studies by Narain et al. (109). This discrepancy might be caused by the relatively low sample size compared with previous meta-analyses. The meta-analysis and systematic review of 22 prospective cohort studies and 10 clinical trials conducted by Malik et al. (8) suggests that long-term consumption of SSBs is linked to weight gain in both children and adults. It should be noted that all these systematic reviews and meta-analyses only examined added sugar in the liquid form (i.e., SSBs), but not sugar in the solid form. Moreover, all observational studies mentioned in this review supporting weight gain in humans after high sugar consumption focused on SSBs (12)(13)(14), which may have a stronger obesogenic effect, as the liquid form of added or free sugars may not be able to induce the compensatory calorie saving that the solid form of sugars could (19). A recent systematic review and meta-analysis of 13 prospective cohort studies (n = 49,591) conducted by Azad et al. (110) examined the associations of both solid and liquid sources of sugar with incidences of MetSyn, and found that while high SSB consumption was linked to an increased incidence of MetSyn (with a moderate certainty of evidence), solid sources of sugar, including ice cream and confectionaries, were not associated with incident MetSyn, although the certainty of evidence was very low. Thus, it is possible that sugar in the solid form does not produce comparable health impacts to SSBs, and more evidence is needed to address this question. Additionally, it was suggested that high sugar consumption is linked to obesity and metabolic diseases due to the provision of excess calories, not the role of sugar itself (7,(111)(112)(113). Individuals who consume a diet high in sugars often have other unhealthy dietary and lifestyle habits, such as a lack of exercise, high fat intake, and smoking, all of which could contribute to the pathogenesis of obesity-related disorders (109,114).

Evidence from clinical trials.
Similar to observational studies, there is also inconsistency in the conclusions from human clinical trials, which may be due to different study designs (Tables 4 and 5). Some studies report that high SSB intake could increase the risks for chronic diseases, such as T2DM, CVD, obesity, hyperglycemia, dyslipidemia, and ectopic fat accumulation (115)(116)(117)(118)(119)(120)(121)(122)(123)(124)(125)(126)(127)(128)(129). Such increases in disease risks were commonly believed to be due to the excess energy contributed by sugars, rather than the unique effect of sugar intake per se. For example, high consumption of SSBs results in increased energy intake and weight gain, overweight, or obesity (n = 41) (120), whereas reduction of SSB intake leads to higher weight loss (116,117), possibly in a dose-dependent manner (116). In another intervention study involving 71 abdominally obese men and lasting for 12 weeks, the researchers found that consumption of moderate amount of fructose (75 g of fructose per day in the form of beverages) led to significant yet small increases Only those in the sugar-sweetened cola group had an increase in serum uric acid level at the end of the intervention (15% increase; P = 0.02) No significant change in body weight or total fat mass was observed in all groups, but the sugar-sweetened cola group had a significant increase in VAT of 30% (P = 0.02), and a more than 2-fold increase in hepatic fat (P    in body weight and waist circumference, as well as increases in the liver fat content. Although the authors did not find any association between changes in energy intake and weight gain, this is likely due to measurement errors or insufficient statistical power, as the statistically nonsignificant increase in daily energy intake (i.e., 54 kcal/day × 84 days = 4536 kcal) should translate into ∼2.5 kg of weight gain (vs. the 1.1 kg reported) (129). Similarly, in a randomized, double-blind study by Johnston et al. (130), during the isocaloric period, high fructose intake (25% daily energy intake) in the form of liquids did not increase weight and liver fat accumulation and disrupt liver function compared to the control group (25% daily energy intake from glucose) in healthy but overweight men. Nevertheless, when on a hypercaloric diet, both high fructose and glucose intake led to similar increases in body weight, liver fat, and biomarkers of liver function.
In contrast, results from some studies suggested that the effects of sugar on these health outcomes were independent of the excess energy contributed by the sugar. For example, a double-blind, randomized controlled trial in 94 healthy men reported that consumption of SSBs containing moderate amounts of fructose or sucrose (80 g/day) increased fatty acid synthesis in the liver even in the basal state, compared to the control group (nonconsumption), without inducing weight gain (127).
Results from studies examining the effects of high sugar consumption on circulating lipids and fat accumulation were also inconsistent. High SSB consumption was found to increase blood TG levels, as well as ectopic fat accumulation in the liver, muscle, and viscera (115,119,(122)(123)(124)129). Sex differences in such effects were also reported in a cross-over trial (n = 16) (118). In contrast, other studies failed to detect a persistent effect of high SSB intake on fasting plasma concentrations of cholesterol, HDL cholesterol, and LDL cholesterol, in both males and females (n = 24) (115), as well as of ectopic lipid accumulation in the liver and muscle (n = 80) (131). It is worth noting that in the latter study, the investigators added different amounts of fructose and HFCS to low-fat milk, which on its own has been shown to benefit cardiometabolic health (132), thus potentially confounding the results. The randomized cross-over trial conducted by Black et al. (133) (n = 13) in healthy subjects also found no significant difference between low-sucrose (10% daily energy intake) and high-sucrose (25% daily energy intake) diets (from both solid and liquid foods) on body weight, insulin sensitivity, fasting plasma glucose and serum insulin, and blood pressure. However, the high-sucrose group had significantly higher total and LDL cholesterol levels than the control group (133). The study by Hieronimus et al. (134) (n = 145) showed that high fructose consumption for 2 weeks led to the greatest increase in TG compared to HFCS, glucose, and aspartame (P = 0.0013 vs. aspartame), and high HFCS consumption led to the greatest increase in LDL cholesterol and apoB compared to fructose, glucose, and aspartame (P = 0.0002 and 0.001, respectively, vs. aspartame). A post hoc assessment found that there was a significant interaction between glucose and fructose in contributing to the significant increases in levels of LDL cholesterol and apoB, but not TG. However, this study has several limitations that affected the validity of conclusions. First, the statistical analysis only compared HFCS and fructose with aspartame, not other types of added or free sugars. Aspartame is a noncaloric, artificial sweetener that is used to replace sugar in foods and beverages, so we are not sure whether HFCS or fructose would also lead to significantly higher increases in cardiovascular risk factors compared to other types of sugars. Second, all sugars examined in this study exist in liquid form, which, as discussed earlier, may have differential impacts on health outcomes. Third, this study lasted only 2 weeks, so it is not known whether the observed effect was going to last over the long term.
Mixed results have also been reported for the effects of high sugar consumption on the macronutrient metabolism. In a randomized, cross-over study conducted in healthy, young males (n = 29) (125), the authors showed that even 6.5% and 13% of daily energy intake consumption of fructose and sucrose, respectively, from SSBs could impair the carbohydrate and lipid metabolisms. However, this study was limited by the short study duration of only 3 weeks and a possible carry-over effect of previous interventions throughout the study. Similarly, moderate (about 13% daily energy intake) consumption of a cola soft drink ingested as part of a mixed meal decreased fat and increased carbohydrate oxidation compared to the control drink (water) (126). However, this study was also limited by a small sample size (n = 8). Lewis et al. (135) compared the effects of high-sucrose (15% daily energy intake) and lowsucrose (5% daily energy intake) diets (from both solid and liquid foods) on body compositions and outcomes of carbohydrate and lipid metabolisms in overweight or obese subjects who were already moderately insulin resistant (n = 13). Their results indicate that there were no differences in body weight, body composition, insulin resistance, lipid profiles, or blood pressure between groups, except the fasting blood glucose level, which was significantly lower in the low-sucrose diet group. In contrast, conclusions from the meta-analysis of 38 randomized controlled trials conducted by Schwingshackl et al. (136) suggest that isocaloric replacement of fructose and sucrose with starch could lead to lower LDL cholesterol levels, insulin resistance, and lower uric acid levels, further adding controversies.
Overall, high SSB intake may increase the risks of T2DM and CVD via induction of hyperglycemia or glucose intolerance and of dyslipidemia due to increased DNL (118,129), circulating TG, VLDL (118,121), and uric acid (5,124). Also, high consumption of fructose-sweetened beverages may disrupt the production of appetite control hormones (decreases in leptin and insulin and increases in ghrelin; n = 12) (123, 128), supporting the differential effects of liquid compared with solid sugars on metabolic and endocrine health.

Limitations of clinical trials.
Several important limitations exist which curtail the validity of conclusions. First, similar to animal studies, most clinical trials are conducted over a short period, which rarely lasts longer than 6 to 8 weeks, although it is acknowledged that subjecting participants to high sugar intake for a longer period may be unethical and impractical, as it is difficult for study participants to adhere to a dietary intervention for a longer period. Second, glucose or fructose alone is used in some studies; however, in real life, they usually coexist in foods (e.g., in HFCS). It has also been pointed out that studies comparing the effects of HFCS with other sweeteners are limited (120). Third, the energy balance is not controlled in some trials; hence, it is impossible to discern whether the observed effects were due to intake of sugar per se or to excessive caloric intake. Fourth, similar to animal studies, many clinical trials examine doses of sugars that are higher than normal human consumption, which is not necessarily realistic and does not lend support to the current guidelines to restrict free sugar intake to below 10% of the daily energy intake. Finally, some clinical trials involved subjects who were overweight or obese or were already hyperglycemic or insulin resistant. Thus, evidence linking high sugar intake with increased risks for chronic diseases comes in part from those who were more susceptible to these diseases, and may not apply to healthy individuals.

Issues with sugar reformulation programs and potential consequences of government policies directed towards reducing sugar intake
We argue that the current public health recommendations to encourage the reduction of both solid and liquid forms of free sugar intake (e.g., sugar reformulation programs that set targets for both solid and liquid foods) should be revised due to the overextrapolation of the results from SSB studies. Moreover, there are other important issues associated with the implementation and effectiveness of sugar reformulation programs. First, sugar has important functional properties in food that other sweeteners cannot completely replace, such as flavor enhancement, color formation, bulk and texture, fermentation, and preservation (137). Second, there are challenges associated with labeling of added sugars, as added sugars cannot be differentiated from total sugars chemically (137) and there is no universal definition for added sugars (138). However, this may not pose a problem for manufacturers, who have the exact formulation of their products. Third, when sugar is removed from a food product, the bulk and texture of the product is usually affected, and bulking agents such as modified starch are commonly utilized to solve the issue. However, these agents generally provide energy because they are carbohydrate-based. As a result, eventually the caloric content could even increase compared to the original formulation (137).

Discussion
While it seems to be a consensus among researchers and public health practitioners that high free sugar consumption, regardless of the sources, is associated with ill health (2,3), in our opinion the substantial limitations in the current body of evidence, especially from animal studies, such as short study durations, the use of supraphysiological doses of sugar or fructose alone, and the lack of appropriate controls, seriously curtail the translatability of the findings to the real-world situation. More studies should also be conducted to further confirm whether free sugars in solid and liquid forms exert similar adverse effects on health. Such studies should be conducted over a longer-term period (at least 6 months) with added and free sugar intakes that better resemble the human diet (20%-25% of daily energy intake). In animal studies that examine the underlying mechanisms of the effects of sugar intake, a lower-sugar diet (e.g., 10% daily energy intake from added or free sugars) should be used as the control diet to better reflect human consumption patterns.
In all, we think the current guidelines on reducing free sugar intake to prevent weight gain and obesity are based on lowquality evidence (7) that requires cautious interpretation by policy-makers and the general public. While some may argue that a high-sugar diet is usually more nutrient dilute (139,140), newer analyses (141-143) suggest an extremely low-sugar diet (<5% daily energy intake) may also have similar nutrientdiluting effects. This is likely because some sugar-rich foods and beverages are indeed a good source of nutrients, such as breakfast cereals. Indeed, sugar may improve the palatability of nutrient-rich foods, such as rolled oats, that are otherwise bland to consume on their own. It is quite possible that "high" sugar consumption at normal dietary doses (e.g., 25% of the daily energy intake), especially in the solid form, may not be uniquely obesogenic or harmful for health. Therefore, the public health emphasis should be on restricting the intakes of specific energydense, nutrient-poor high-sugar foods, such as cakes and biscuits, rather than limiting sugar intake from all foods. To date, many countries have implemented taxes on SSBs. While this has been effective in reducing SSB consumption, whether the tax is also effective in preventing obesity and cardiometabolic diseases is still questionable based on the major limitations in the current body of evidence (144). Also, although low-calorie artificial sweeteners provide significantly less energy than sugars and have been widely used in food products as an alternative to sugars (145,146), a number of studies have shown that these sugar substitutes could cause weight gain, cancers, and side effects, and more welldesigned, large-scale human studies on the health effects of lowcalorie artificial sweeteners are needed in the future (147).
The authors' responsibilities were as follows -JCYL, CBC: conceived the idea of the article; RY: conducted the literature search and wrote the first draft; JCYL: is the guarantor of this work and has primary responsibility for the final content; and all authors: provided substantial intellectual input into the edits of the article and read and approved the final manuscript. RRY is supported by the Hong Kong PhD Fellowship from the Research Grants Council, HKSAR. All other authors report no conflicts of interest.